Lysosomes are the cellular components involved in removing misfolded/aggregating proteins, but with aging, lysosomes become less effective at clearing toxic accumulations that are linked to the deterioration of neuronal connections. For example, a recent study using a model of proteasome stress in rat hippocampus showed that the level of cathepsin B, a lysosomal cysteine protease, increased in response to proteolytic stress in young rats but not in aged rats (Gavilán et al. (2015) “Age-related dysfunction of the autophagy lysosomal pathway in hippocampal pyramidal neurons under proteasome stress” Neurobiol Aging. 36:1953-1963). In vivo, it has also been shown that cathepsin B activity significantly increased in young and middle-aged, but not elderly mice that express human amyloid beta (Aβ) precursor protein (hAPP) as compared to age-matched nontransgenic control mice (Mueller-Steiner S, Zhou Y, Roberson E D, Sun B, Chen J, et al. (2006) Antiamyloidogenic and neuroprotective functions of cathepsin B: Implications for Alzheimer's disease. Neuron 51: 703-714).
Protein accumulation disorders, including Alzheimer's disease (AD), frontotemporal dementia (FTD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and other dementias, are suspected to involve imbalances between protein production and protein clearance.
For example, synaptic pathology that disrupts neuronal connectivity has long been considered the key event in age-related disorders that 1) leads to cognitive deficits and 2) contributes to early, gradual changes that constitute risk factors for dementia.
Alzheimer's disease is characterized by a progressive inexorable loss of cognitive function. AD is characterized by two neuropathological hallmarks: excessive number of senile plaques in the cerebral cortex and subcortical gray matter which contains β-amyloid, and neurofibrillary tangles consisting of tau protein. In one study, researchers found that increased cathepsin B activity is associated with reduced β-amyloid accumulation and suggested using cilostazol, an agent shown to increase cathepsin B activity, for treating patients with A D (Park S Y, Lee H R, Lee W S, Shin H K, Kim H Y, Hong K W, et al. (2016) Cilostazol Modulates Autophagic Degradation of β-Amyloid Peptide via SIRT1-Coupled LKB1/AMPKα Signaling in Neuronal Cells. PLoS ONE 11(8): e0160620).
Heart failure is the leading cause of death in the developed world, and it represents a common endpoint for several diseases, including hypertension, coronary artery disease, and the cardiomyopathies. A lack of pathogenic commonality is underscored by the large number of mutations in different classes of cardiac proteins that have been linked to dilated and hypertrophic cardiomyopathy (HCM).
Amyloid oligomers are present in cardiomyocytes derived from human heart-failure subjects and in animal models of cardiomyopathy. From a study using cardiac stem cells cultured from explanted failing hearts, the authors suggested increasing cathepsin B activity as a way to protect heart cells (Gianfranceschi et al. (2016) “Critical role of lysosomes in the dysfunction of human Cardiac Stem Cells obtained from failing hearts” Int. J. Cardiol. 216:140-50).
There has been a line of studies suggesting that enhancement of cathepsin B activity is a compensatory event in response to protein accumulation stress. For example, in Gavilán et al., it was shown that cathepsin B increased in response to proteasome stress in young rats with brain-injected lactacystin (Gavilán et al., 2015). In Bendiske & Bahr, it was shown that cathepsin B increased in response to chloroquine-induced protein accumulation stress in hippocampal slices (Bendiske J, Bahr B A (2003) Lysosomal activation is a compensatory response against protein accumulation and synaptopathogenesis—An approach for slowing Alzheimer's disease? J Neuropathol Exp Neurol 62: 451-463).
Improved methods for treating protein accumulation diseases are needed.